Many people - and especially Veterans - have at some time sustained traumatic injury to the joint, and this injury often leads to the development of post-traumatic osteoarthritis (OA) in the affected joint(s) years later. No treatments exist that can promote healing and prevent the development of OA following traumatic joint injury. Moreover, current therapies for those who have developed OA simply alleviate symptoms of advanced disease rather than inhibit the processes that drive the disease. A better understanding of the mechanisms underlying the pathogenesis of post-traumatic OA would undoubtedly yield new therapeutic approaches. Coagulation and fibrinolysis - two closely linked proteolytic cascades that regulate bleeding - are aberrantly activated in the joints of individuals with late-stage OA. We found that pharmacological inhibition of the key fibrinolysis factor plasmin attenuated post-traumatic OA and its attendant synovial inflammation in mice, as did deficiency in tissue plasminogen activator (tPA), an endogenous inducer of plasmin generation. Conversely, deficiency in plasmin activator inhibitor 1 (PAI-1), the endogenous inhibitor of plasmin generation, had the opposite effect. In addition, carboxypeptidase B (CPB), an enzyme that links coagulation and inflammation was activated in the synovial fluid of individuals with OA and protected against post-traumatic OA in mice. Furthermore, the coagulation factors thrombin and fibrinogen stimulated the production of degradative enzymes and inflammatory cytokines by fibroblast-like synoviocytes from OA patients. We hypothesize that, rather than being an epiphenomenon of late-stage OA, deregulation of the coagulation-fibrinolysis systems is a primary event that is crucial to the pathogenesis of OA. We hypothesize that coagulation and fibrinolysis factors promote the low-grade inflammation that drives OA. We propose to elucidate the roles of coagulation and fibrinolysis in post-traumatic OA. The availability of several FDA-approved anticoagulants and antifibrinolytics means that success of these studies could, with relative ease, lead to development of the first-ever preventive therapies for post-traumatic OA. We propose to determine whether short-term administration of specific anticoagulants or antifibrinolytics after traumatic joint injury or after development of early signs of OA can reset the coagulation-fibrinolysis system in the synovial joints and thereby prevent or treat post-traumatic OA. PUBLIC HEALTH RELEVANCE: Relevance of the proposed research to Veterans' health: Many military personnel and Veterans incur traumatic joint injuries that result in joint dysfunction and lead to the development of post traumatic osteoarthritis (OA). Our findings suggest that the coagulation-fibrinolysis system plays a critical role in the development of post-traumatic OA. Specifically, the activation of the coagulation-fibrinolysis system induces the production of inflammatory and degradative mediators. The success of these studies could lead to novel therapeutic approaches to prevent development of and to treat OA following traumatic joint injury.